1. Field of the Invention
This invention relates to modified release dosage forms such as modified release pharmaceutical compositions. More particularly, this invention relates to modified release dosage forms having partial coatings, for example dosage forms partially coated by first material for controlling the surface area through which dissolution of at least one active ingredient contained within the dosage form takes place upon contacting of the dosage form with a liquid medium.
2. Background Information
Modified release pharmaceutical dosage forms have long been used to optimize drug delivery and enhance patient compliance, especially by reducing the number of doses of medicine the patient must take in a day. For this purpose, it is often desirable to modify the rate of release of drug (one preferred type of active ingredient) from a dosage form into the gastrointestinal (g.i.) fluids of a patient, especially to slow the release to provide prolonged action of the drug in the body. In many cases, it is particularly desirable to provide a constant (i.e. zero-order) release rate of the drug. For patients taking a particular medication on a chronic basis, matching the rate of drug absorption into the circulatory system with its rate of metabolism and excretion from the body could enable achievement of a steady state in which a relatively constant level of drug is maintained in the blood. This can have the advantageous effect of minimizing undesirable side effects which may occur at high blood levels, while maintaining a therapeutic level of the active ingredient (e.g. drug) in the body.
The rate at which an orally delivered pharmaceutical active ingredient reaches its site of action in the body depends on a number of factors, including the rate and extent of drug absorption through the g.i. mucosa. To be absorbed into the circulatory system (blood), the drug must first be dissolved in the g.i. fluids. For many drugs, diffusion across the g.i. membranes is relatively rapid compared to dissolution. In these cases, the dissolution of the active ingredient is the rate limiting step in drug absorption, and controlling the rate of dissolution allows the formulator to control the rate of drug absorption into the circulatory system of a patient.
The dissolution rate of a drug in the g.i. fluids depends, among other things, on the drug's solubility and the effective surface area of contact between dissolving drug particles and the dissolution medium. The Nernst-Brunner equation describes the dissolution rate of a drug:dC/dt=(D K2 S) (1/vh) (Cs−Ct)where dC/dt is the drug dissolution rate, D is the diffusion coefficient for the drug, K is a dissolution constant, h is the effective thickness of the diffusion layer, S is the surface area of contact between the drug and the dissolution medium, Cs is the solubility of the drug in the medium (i.e. the concentration of a saturated solution at the surface of the dissolving particle), and Ct is the concentration of drug in the bulk solution at a time t. In the body, the absorption process constantly removes drug from the g.i. tract, usually at a rate faster than that of drug dissolution. This creates what is known as a “sink” condition, where Cs, the concentration of drug in the bulk solution, is much less than Cs, the concentration of drug in the saturated region at the surface of the dissolving particle.
The primary non-constant terms in this model are S, the surface area of contact between the drug and the dissolution medium, and h, the effective thickness of the diffusion layer. In a typical sustained release matrix tablet, the surface area of contact between the drug and dissolution medium decreases over time, while in a diffusional matrix system, the path-length for diffusion increases over time, as the dissolution “front” recedes from the surface towards the center of the dosage form. The combination of these effects results in a decrease in dissolution rate of the drug over time.
Various dosage forms have been proposed to approach a constant dissolution rate by employing dosage form shapes in which the surface area of contact between the drug and dissolution medium increase at the same rate as the path-length for diffusion. Most involve coating a portion of the dosage form with an impermeable layer to control the surface area available for dissolution of the drug. See for example, U.S. Pat. Nos. 3,146,169; 3,851,638; 4,663,147; 4,816,262; and 6,110,500. One shape of particular interest has been that of a torus. Another has been that of a truncated cone. The primary limitation of such designs has been laborious manufacturing processes which typically include making a core, coating the core with impermeable material, then removing a portion of the core and coating to create the area for drug dissolution. These types of processes have not been shown to be suitable for commercial scale manufacture.
U.S. Pat. No. 4,803,076 discloses a tablet press for use in the manufacture of a tablet in the approximate shape of a truncated cone, as well as an apparatus for removal of a portion of the coated dosage form in order to expose an area for dissolution of the drug. However, the dosage form disclosed therein suffers from the limitation of possessing a flat cylinder or disc shaped central portion, defined by the straight die walls, and a “land” area defined by the perimeter of the upper and lower punches in the compression machine.
There remains an unmet need for a commercially efficient method of producing a partial coating on a dosage form. Such partial coatings would be useful for controlling the surface area through which drug is released from the dosage form, including providing a surface area for drug release from the dosage form that remains constant during the drug release period; and providing a surface area for drug release from the dosage form that increases during the drug release period. The apparatus and methods described in copending U.S. patent application Ser. No. 09/966,497, pages 27-51 and Ser. No. 09/966,450, pages 57-63, the disclosures of which are incorporated herein by reference, advantageously enable manufacture of partially coated dosage forms without the need for a partial coating removal step.
It would additionally be desirable to have a method for making such partially coated dosage forms with a further shell portion, residing upon at least a portion of the uncoated core surface, for example to deliver an immediate release loading dose of one or more active ingredients; or to confer a unique elegant appearance. It would be particularly desirable for the shell portion to reside upon and cover only the uncoated portion of the core surface, and not the first coating material. In would further be desirable to make the shell portion optionally removable by the consumer or healthcare professional prior to ingestion of the dosage form in order to customize dosing. Another beneficial use for such partially coated dosage forms include as containers for holding liquid or solid materials, which may be removed from the dosage form for example by removing the shell portion, and pouring through the uncoated portion prior to use. It would additionally be desirable to have a modified release dosage form comprising an inactive core having a specialized shape or structure, and comprising for example swelling or gelling excipients, which effect the release of active ingredient from one or more shell compartments.
It would also be desirable to coat non-conventionally shaped dosage forms that provide constant controlled release rates by virtue of their shape with a shell of a more regular shape to facilitate swallowing, or reduce friability (susceptibility to breakage). For example it would be useful to have dosage forms comprising a core in the shape of a torus or truncated cone containing an active ingredient therein, protected by a spheroid or elypsoid shaped shell. Such dosage forms would be easy to swallow, maintain their structural integrity during handling and shipping, and yet provide the functional benefits conferred by the shape of the core. The apparatus and methods of copending U.S. patent application Ser. No. 09/966,497, pages 27-51 and Ser. No. 09/966,450, pages 57-63 advantageously enable the production of such dosage forms according to this invention.
It is one object of this invention to provide a dosage form in which at least one active ingredient contained therein exhibits a modified release profile upon contacting of the dosage form with a liquid medium. It is another object of this invention to provide a dosage form in which the surface area for dissolution of at least one active ingredient contained therein is controlled by a partial coating. Other objects features and advantages of the invention will be apparent to those skilled in the art from the detailed description set forth below.